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(C-6), 56.7 (C-2), 109.4 (C-4), 196.7 (C-5), 199.1 (C-3), 201.7 (CH3C]
O), 210.0 (C-1).
(C(CH3)2), 48.6 (CH2), 52.2 (CH2), 55.1 (C(CH3)2), 98.0 (C-500), 103.7
(CAr), 109.0 (CAr), 114.7 (C-4), 158.8 (COHAr), 162.9 (COHAr), 164.1
(COHAr), 176.6 (C-3, enol), 203.1 (C-3, keto form), 206.3 (C-1000),
212.5 (C-1); HRMS: calcd for C26H36O7 461.25338 [MþNa]þ, found
461.25290.
4.4. 5-Hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione
(syncarpic acid)15 (4)
A suspension of acylsyncarpic acid (9) (30.4 g, 0.136 mol) in 3 M
HCl (1.4 L) was refluxed for 6 h until the starting material had
disappeared (TLC control). Thereafter, the mixture was cooled
down to room temperature and extracted with ethyl acetate
(4ꢁ400 mL). The combined organic layers were washed twice with
water, dried over Na2SO4, filtered and concentrated in vacuo. The
crude product was recrystallized from toluene to provide syncarpic
acid (4) (18.3 g, 74%) as pale yellow crystals. Rf¼0.37 (petroleum
ether/ethyl acetate,1:1); 1H NMR (400 MHz, CDCl3), mixture of keto
4.6. Rhodomyrtosone B (2)
A solution of compound 3 (59 mg, 0.128 mmol) in benzene
(5 mL) was refluxed in presence of
a catalytic amount of
p-TsOH$H2O (1.2 mg, 5 mol %) for 1 h (reaction progress was fol-
lowed by TLC). After the mixture was cooled down, water (20 mL)
was added, and the product was extracted using diethyl ether
(3ꢁ10 mL). The combined organic layers were dried over MgSO4,
filtered and concentrated in vacuo. Purification by preparative TLC
(petroleum ether/ethyl acetate, 4:1) provided 39 mg (69%) of rho-
domyrtosone B (2) as an orange oil. Rf¼0.4 (petroleum ether/ethyl
and enol tautomers in a ratio of w2:1; keto tautomer: d 1.31 (s, 12H,
4CH3), 3.61 (s, 2H, CH2); enol tautomer:
d 1.40 (s, 12H, 4CH3), 5.74
(br d, J¼2.3 Hz, 1H, CH), 8.00 (br s, 1H, OH); 13C NMR (100 MHz,
acetate, 4:1); 1H NMR (400 MHz, CDCl3):
d
0.85 (d, J¼6.3 Hz, 3H, 200-
CDCl3): keto tautomer:
d
21.8 (4CH3), 50.2 (CH2), 59.1 (2C(CH3)2),
CH3), 0.86 (d, J¼6.3 Hz, 3H, 200-CH3), 0.99 (d, J¼6.6 Hz, 3H, 30-CH3),
1.01 (d, J¼6.6 Hz, 3H, 30-CH3), 1.38, 1.41, 1.46, 1.62 (4s, 12H, 4CH3),
w1.35 (obscured,1H, 200-H), w1.35 (obscured, 2H,100-H), 2.35 (qqdd,
J¼6.8, 6.8, 6.6, 6.6 Hz, 1H, 30-H), 2.93 (dd, J¼17.2, 6.1 Hz, 1H, 20-H),
3.17 (dd, J¼17.2, 7.3 Hz, 1H, 20-H), 4.29 (t, J¼6.1 Hz, 1H, 9-H), 6.25 (s,
1H, 7-H), 8.08 (s, 1H, OH), 13.49 (s, 1H, OH); 13C NMR (100 MHz,
204.3 (2C]O), 208.9 (C]O); enol tautomer: d 24.6 (4CH3), 51.2 (C-
6), 59.1 (2C(CH3)2), 101.7 (C-4), 191.9 (C-5), 204.3 (C-3), 212.6 (C-1).
4.5. 5-Hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-
trihydroxy-3-(3-methylbutanoyl)phenyl)butyl)-cyclohex-4-
ene-1,3-dione (3)
CDCl3):
d
22.6 (30-CH3), 22.9 (30-CH3), 23.1 (200-CH3), 23.4 (200-CH3),
24.3 (2-CH3), 24.4 (2-CH3), 24.4 (C-30), 24.7 (4-CH3), 24.8 (C-200),
25.0 (C-9), 25.3 (4-CH3), 46.9 (C-100), 47.2 (C-4), 53.4 (C-20), 56.1 (C-
2), 100.0 (C-7), 105.3 (C-5), 106.0 (C-8a), 114.6 (C-9a), 153.1 (C-10a),
160.1 (C-6), 164.3 (C-8), 167.3 (C-4a), 198.4 (C-1), 203.9 (C-10), 211.9
(C-3); HRMS: calcd for C26H34O6 465.22476 [MþNa]þ, found
465.22422.
4.5.1. Knoevenagel condensation to give 2,2,4,4-tetramethyl-6-(3-
methylbutylidene)cyclohexane-1,3,5-trione (10). To a suspension
of syncarpic acid (4) (6.76 g, 0.037 mol) in CH2Cl2 (110 mL) was
added isovaleraldehyde (6 mL, 0.056 mol, 1.5 equiv) followed by
dropwise addition of piperidine (7.4 mL, 0.075 mol, 2 equiv) at
room temperature. After being stirred for 10 min, the reaction
mixture was quenched with 1 M HCl (50 mL) and saturated am-
monium chloride solution (50 mL) and stirred vigorously for 1 h.
This mixture was extracted with CH2Cl2 (3ꢁ150 mL). The com-
bined organic layers were dried over Na2SO4, filtered, and con-
centrated in vacuo. The crude enetrione 10 was passed through
short pad (5 cm) of flash silica-gel using CH2Cl2 as eluent. Due to its
propensity towards isomerization, this enone was used immedi-
ately for the next step.
4.7. 6,8-Dihydroxy-9-isobutyl-2,2,4,4-tetramethyl-4,9-
dihydro-1H-xanthene-1,3(2H)-dione (11)
If the previous procedure is changed in that an excess of p-
TsOH$H2O (3 equiv) is used and the reaction time is prolonged to
3 h, retro FriedeleCrafts reaction takes place. Thus, to a solution of 3
(2.0 g, 4.34 mmol) in benzene (60 mL), p-TsOH$H2O (2.48 g,
13.03 mmol, 3 equiv) was added and the mixture was refluxed for
3 h. After the mixture was cooled down, water (160 mL) was added,
and the product was extracted using diethyl ether (3ꢁ50 mL). The
combined organic layers were dried over MgSO4, filtered and
concentrated in vacuo. After recrystallization of the crude product
using toluene, xanthene derivative 11 (0.95 g, 61%) was obtained as
yellowish crystals, which are slightly soluble in CH2Cl2. Rf¼0.29
(petroleum ether/ethyl acetate, 2:1); 1H NMR (400 MHz, acetone-
4.5.2. Michael addition to give 5-hydroxy-2,2,6,6-tetramethyl-4-(3-
methyl-1-(2,4,6-trihydroxy-3-(3-methylbutanoyl)phenyl)butyl)cyclo-
hex-4-ene-1,3-dione (3). The crude enetrione 10 (about 0.035 mol)
from the previous step was dissolved in dry THF (75 mL) and added
slowly by syringe pump within 20 min to a stirred solution of
isovalerylphloroglucinol (6) (6.0 g, 0.029 mol) in THF (60 mL) to
which previously 95% sodium hydride (722 mg, 0.029 mol, 1 equiv)
had been added. After being stirred for 1 h, the reaction was
quenched with saturated NH4Cl solution and the mixture was
extracted with diethyl ether (4ꢁ200 mL). The combined organic
layers were dried over MgSO4, filtered and concentrated in vacuo.
The crude yellow oil was purified by flash chromatography (CH2Cl2/
methanol, 200:1) to give the title compound 3 (5.6 g, 42%) as
a yellow solid. Rf¼0.26 (CH2Cl2/MeOH, 100:1); 1H NMR (400 MHz,
d6):
d
0.80 (d, J¼6.3 Hz, 3H, 20-CH3), 0.83 (d, J¼6.6 Hz, 3H, 20-CH3),
1.30, 1.32, 1.43, 1.51 (4s, 12H, 4CH3), 1.36e1.43 (m, 1H, 10-H),
1.37e1.48 (m, 1H, 20-H), 1.51e1.59 (m, 1H, 10-H), 4.21 (t, J¼5.8 Hz,
1H, 9-H), 6.19 (d, J¼2.3 Hz, 1H, 5-H), 6.28 (d, J¼2.3 Hz, 1H, 7-H), 8.34
(d, J¼1.3 Hz, 1H, OH), 8.67 (d, J¼1.3 Hz, 1H, OH); 13C NMR (100 MHz,
acetone-d6):
d
24.2 (20-CH3), 24.6 (20-CH3), 25.0 (2-CH3), 25.3 (2-
CH3), 25.6 (C-20), 25.7 (4-CH3), 26.2 (4-CH3), 26.9 (C-9), 47.6 (C-
10), 48.4 (C-4), 56.9 (C-2), 96.2 (C-5), 100.6 (C-7), 106.6 (C-8a), 115.0
(5C), 154.2 (C-10a), 157.0 (C-6), 158.5 (C-8), 167.0 (C-4a), 198.1 (C-1),
213.3 (C-3); HRMS: calcd for C21H26O5 381.16725 [MþNa]þ, found
381.16638.
CDCl3):
d
0.83 (d, J¼6.6 Hz, 3H, 30-CH3), 0.85 (d, J¼6.6 Hz, 3H, 30-
CH3), 0.98 (d, J¼6.8 Hz, 6H, 2(3000-CH3)), 1.32, 1.33, 1.38, 1.48 (4s, 12H,
4CH3), w1.37 (obscured, 1H, 30-H), 1.72e1.81 (m, 1H, 20-H),
2.03e2.12 (m, 1H, 20-H), 2.26 (qqdd, J¼6.8, 6.8, 6.6, 6.6 Hz, 1H, 3000-
H), 2.96 (d, J¼6.6 Hz, 2H, 2000-H), 4.36 (t, J¼7.7 Hz, 1H, 10-H), further
peaks show ketoeenol tautomerism in a ratio of 3:7; enol tauto-
4.8. 6,8-Dihydroxy-9-isobutyl-2,2,4,4-tetramethyl-4,9-
dihydro-1H-xanthene-1,3(2H)-dione (11) from phloroglucinol
and enetrione 10
mer:
(s, 1H, OH); keto tautomer:
10.55 (s, 1H, OH), 11.20 (s, 1H, OH); 13C NMR (100 MHz, CDCl3):
22.3 (CH3), 22.5 (CH3), 22.8 (2CH3), 24.3 (CH3), 25.3 (CH3), 26.1
(CH3), 26.9 (CH3), 27.0 (CH, i-Pr), 27.9 (CH, i-Pr), 31.0 (C-10), 38.2
d
5.89 (s, 1H, 500-H), 6.39 (br s, 1H, OH), 10.33 (s, 1H, OH), 11.58
5.95 (s, 1H, 500-H), 6.39 (br s, 1H, OH),
d
As described above, syncarpic acid (4) (1.083 g, 5.94 mmol) was
converted to enetrione 10 using isovaleraldehyde (0.95 mL,
8.83 mmol, 1.5 equiv) and piperidine (1.18 mL, 11.92 mmol, 2 equiv)
d